The long-term goal of this SCOR investigating the form of acute lung injury known as adult respiratory distress syndrome (ARDS) is to design and test interventions which reduce the incidence, severity, and complications of acute lung injury. We plan to approach this goal by performing multi-disciplinary research which will result in an improved understanding of the mechanisms of inflammation involved in acute lung injury and correlating this information with data on the clinical epidemiology of ARDS. We hypothesize that, although initial lung injury involves inflammatory mechanisms, when lung inflammation evolves in a normal orderly sequence the injury is limited, the repair process is facilitated, and recovery to normal function occurs. The primary hypothesis that we intend to test is that sustained alveolar inflammation following the initial injury prevents resolution of lung injury in a timely and orderly sequence and is responsible for further propagation of that injury. We believe that clinically this is associated with increased complications including infection, multiple organ failure, and death; those patients with sustained inflammation who do survive will have an increased incidence of long-term pulmonary dysfunction. We hypothesize that this phenomenon of sustained "rogue inflammation occurs more commonly in patients whose ARDS is associated with sepsis than with trauma. All of the individual projects investigate specific aspects of the inflammatory process and its perturbations. The approach of this SCOR proposal is multi-disciplinary. Research disciplines include cellular immunology and biology, molecular biology, biochemistry, physiology, morphology, and clinical epidemiology and biostatistics. The investigators have been trained in these investigative fields and are in the Departments of Medicine, Surgery, Pediatrics, Anesthesiology, and Pathology of the School of Medicine and the Department of Health Services of the School of Public Health. This proposal is the result of a long and continuing interest in acute lung injury research by the investigators and is based on a strong history of productive collaboration among these investigators. Particular strengths of this proposal include the experience and productivity of the investigators in ARDS and inflammation-related research, the strong collaboration between clinical and basic science investigators, proven access to ARDS patient populations including patients with trauma and sepsis syndrome, and the existence of an established clinical data collection system and experience with an ARDS database.